Selenium (Se) is an essential micronutrient in mammals tiiat exerts its function in the context of selenocysteine-containing proteins. The group of selenoproteins is represented by more than 50 protein families; however, they all appear to contribute to antioxidant and redox regulation by being selenoprotein forms of thiol oxidoreductases. The human selenoproteome consists of 25 selenoproteins which are involved in protection against oxidative stress, signal transduction, and the folding, modification, and regulation of proteins. Selenoprotein expression depends on dietary Se content. Intriguingly, recent clinical trials suggest that Se over-nutrition may significantly raise the risk of type 2 diabetes development. Subsequent studies involving mouse models demonstrated that low and high Se intake are both associated with the type 2 diabetes-like phenotype; however, specific mechanisms of this phenomenon have not been investigated. Different regions of the world are characterized by significant variations in Se content in soil and the associated variation in dietary Se content. Many regions of the United States are Se-rich, and the United States population is characterized by high levels of Se in plasma and, therefore, may have increased risk of diabetes development. In addition, the use of Se-rich dietary supplements in such areas may have a negative impact on health and increase the incidence of diabetes. The goal of this project is to investigate the roles of Se and selenoproteins in redox regulation of glucose homeostasis. The central hypothesis is that Se regulates selenoprotein synthesis which, in turn, alters redox homeostasis and influences the insulin signaling pathways. Specifically, Dr. Fomenko will define the effects of Se supplementation on redox-dependent insulin signaling. This work will be guided by two specific aims: (1) identify mechanisms underlying Se-dependent type 2 diabetes development; and (2) assess the contribution of selenoproteins to H2O2 signaling and associated control of glucose homeostasis. These aims will be addressed using a combination of biochemical and cell biology studies and animal models. The proposed study fits with the mission of the Nebraska Center for the Prevention of Obesity Diseases through Dietary Molecules (NPOD) and will help identify mechanisms of Se micronutrient-associated diabetes development. NPOD support, facilities, and mentoring will allow Dr. Fomenko to advance this project toward an independent R01 award and achieve his long-term research goals in Se biology.